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Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or w...

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Main Authors: Tauziède-Espariat, Arnault (Author) , Siegfried, Aurore (Author) , Nicaise, Yvan (Author) , Kergrohen, Thomas (Author) , Sievers, Philipp (Author) , Vasiljevic, Alexandre (Author) , Roux, Alexandre (Author) , Dezamis, Edouard (Author) , Benevello, Chiara (Author) , Machet, Marie-Christine (Author) , Michalak, Sophie (Author) , Puiseux, Chloe (Author) , Llamas-Gutierrez, Francisco (Author) , Leblond, Pierre (Author) , Bourdeaut, Franck (Author) , Grill, Jacques (Author) , Dufour, Christelle (Author) , Guerrini-Rousseau, Léa (Author) , Abbou, Samuel (Author) , Dangouloff-Ros, Volodia (Author) , Boddaert, Nathalie (Author) , Saffroy, Raphaël (Author) , Hasty, Lauren (Author) , Wahler, Ellen (Author) , Pagès, Mélanie (Author) , Andreiuolo, Felipe (Author) , Lechapt, Emmanuèle (Author) , Chrétien, Fabrice (Author) , Blauwblomme, Thomas (Author) , Beccaria, Kévin (Author) , Pallud, Johan (Author) , Puget, Stéphanie (Author) , Uro-Coste, Emmanuelle (Author) , Varlet, Pascale (Author)
Format: Article (Journal)
Language:English
Published: 13 August 2021
In: Acta Neuropathologica Communications
Year: 2021, Volume: 9, Pages: 1-13
ISSN:2051-5960
DOI:10.1186/s40478-021-01238-y
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1186/s40478-021-01238-y
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Author Notes:Arnault Tauziède-Espariat, Aurore Siegfried, Yvan Nicaise, Thomas Kergrohen, Philipp Sievers, Alexandre Vasiljevic, Alexandre Roux, Edouard Dezamis, Chiara Benevello, Marie-Christine Machet, Sophie Michalak, Chloe Puiseux, Francisco Llamas-Gutierrez, Pierre Leblond, Franck Bourdeaut, Jacques Grill, Christelle Dufour, Léa Guerrini-Rousseau, Samuel Abbou, Volodia Dangouloff-Ros, Nathalie Boddaert, Raphaël Saffroy, Lauren Hasty, Ellen Wahler, Mélanie Pagès, Felipe Andreiuolo, Emmanuèle Lechapt, Fabrice Chrétien, Thomas Blauwblomme, Kévin Beccaria, Johan Pallud, Stéphanie Puget, Emmanuelle Uro-Coste and Pascale Varlet, on behalf of the RENOCLIP‑LOC the BIOMECA (Biomarkers for Ependymomas in Children, Adolescents) consortium
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Summary:The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.
Item Description:Gesehen am 09.11.2021
Physical Description:Online Resource
ISSN:2051-5960
DOI:10.1186/s40478-021-01238-y

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